The global prevalence of obesity has increased dramatically worldwide including Korea over the last decades and has now reached epidemic proportions (16). According to the World Health Organization, 35% of adults worldwide aged >20 years were overweight (34% men and 35% women) in 2008.
Obesity is a metabolic disease and characterized as the accumulation of excessive body fat by hypertrophy and hyperplasia of adipocytes (17). Many factors that can cause obesity include an intake of high calorice meals, genetic defects, disorders of hormonale secretions and a lack of activity. Obesity is involved in the onset of various diseases, including coronary heart disease, hypertension type II diabetes, stroke, gallbladder disease, and osteoarthritis (18-22).
Adipose tissue is an endocrine organ that secretes adipokines to regulate nutrient homeostasis (23, 24). Leptin is an adipokine and a multi-functional cytokine. It is an endocrine hormone and suppresses appetite. It induces the expression of proopiomelanocortin (POMC) via binding to leptin receptor expressed on the neuronal cells in the hypothalamus. Serum leptin levels are regulated by fat mass, if weight is reduced, concentration of leptin is decreased that increases appetites and decreases energy expenditure. Reversely, increased fat more secrets leptin which reduces appetites. Adipose tissue-released leptin binds to the leptin receptor (ObR) which is expressed on the surface of neuronal cells through the blood-brain barrier (BBB). ObR is expressed most cells and contains extracellular domain including leptin binding site and intracellular domain associated with janus kinase2 (JAK2). Several signal transducers and activators of transcriptions (STATs) including STAT1, STATS, and STATS can bind to ObR. In addition, Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) also binds to ObR. When leptin binds to ObR, JAK2 is activated and phosphorylated. The activated JAK2 phosphorylates tyrosine residues positioned at 985, 1077, 1138 on ObR and recruits and phosphorylates down-stream signaling molecules. Phosphorylated STATs are dimerized and translocated from cytosol to the nucleus and induces the expression of target genes. This signaling ultimately decreases food intake and weight loss (25-27). Previously, leptin was developed as anti-obesity drug but this trial was failed due to existence of leptin resistance in obese humans. In the obese environment, serum leptin levels increase, and promote leptin resistance that leads to more severe obesity (28). Leptin resistance has been the main reason behind the unsuccessful application of leptin as an anti-obesity agent. Leptin signaling induces the expression of suppressor of cytokine signaling 3 (SOCS3), which is an endogenous negative feedback inhibitor (29-31). SOCS3 binds to an intracellular domain of ObR via SH2 domain and suppresses leptin signaling through inhibition of JAK activity and degradation of ObR. According to the previous studies, neuronal deletion of SOCS3 prevented leptin resistance in animal on high fat diet (32, 33).